HPV Status May Predict Response and Survival in Oropharyngeal Cancer

Action Points

Explain to interested patients that elevated levels of human papillomavirus have been associated with better outcomes in patients with advanced oropharyngeal cancer.

Note that these studies involved only a small number of patients.

ANN ARBOR, Mich., May 13 -- In patients with advanced oropharyngeal cancer, elevated levels of human papillomavirus (HPV) identify a potentially large subgroup that has a high likelihood of response and favorable prognosis, investigators here found.

High HPV titer was a significant predictor of response to induction chemotherapy and chemoradiation, overall survival, and disease-specific survival, Francis P. Worden, M.D., of the University of Michigan, and colleagues reported online in the Journal of Clinical Oncology.

Two-thirds of biopsy specimens tested positive for HPV, and 90% of HPV-positive patients responded to induction chemotherapy and chemoradiation.

The investigators also found evidence supporting vaccination of adolescent boys against HPV: Almost three-fourths of men had HPV-positive tumors, compared with about 40% of women.

In a related study also published online, the Michigan researchers reported that the combination of low-level expression of epidermal growth factor receptor (EGFR) and high expression of the kinase inhibitor p16 predicted a good response to organ-sparing therapy and favorable outcome. Increased expression of p16 also is associated with a higher titer of HPV.

The incidence of oral and oropharyngeal cancer is increasing in the United States. Although tobacco and alcohol remain the strongest risk factors, HPV, particularly HPV16, has emerged as a major etiologic factor, the authors said.

Some studies have shown better outcomes for patients with HPV-positive head and neck cancer, they continued, but the results have not been consistent, the authors continued.

So, in an effort to clarify the association between HPV and oropharyngeal cancer, the researchers designed a clinical study in which response to induction chemotherapy was used to select patients for chemoradiation.

The study involved 66 patients with stage III/IV squamous-cell oropharyngeal cancer. Patients received a single cycle of induction chemotherapy that consisted of a platinum agent plus 5-fluorouracil.

Patients who had greater than a 50% response received chemoradiation (70 Gy in 35 fractions and concurrent platinum chemotherapy). Those who had complete histologic responses received adjuvant paclitaxel. In the event of a less robust response, patients underwent definitive surgery and received postoperative radiation.

Investigators also tested 42 pretreatment biopsy specimens for HPV.

Among the 66 patients, 54 (81%) met response criteria for chemoradiation, and 53 of those received the treatment. Complete histologic response occurred in 49 (92%) patients, and 78.6% of patients had organ preservation.

After a median follow-up of 64.1 months, the four-year overall survival was 70.4%, and the disease-specific survival was 75.8%.

HPV16 was found in 64.3% of biopsy specimens. HPV titer had a significant association with response to induction therapy (P=0.001) and to chemoradiation (P=0.005), overall survival (P=0.007), and disease-specific survival (P=0.008).

Biopsies from male patients tested positive for HPV in 22 of 30 cases (73.3%) compared with five of 12 biopsies from female patients (41.7%). HPV also was associated with nonsmoking status (P=0.037).

"The factors that govern response to [induction chemotherapy] and subsequent response to [chemoradiation] are poorly understood," the authors said. "However, it is clear that HPV positive tumors were most likely to respond . . . All HPV-negative patients were former or current smokers. For reasons that are not entirely clear, smoking decreases the advantage of having an HPV positive tumor."

The second article from the Michigan group focused on identification of predictive markers in the 42 pretreatment biopsy specimens.

The investigators examined the specimens for expression of EGFR, p16, BCLXL, p53, and p53 mutation. The markers also were evaluated for associations with HPV, treatment response, and survival.

EGFR expression correlated inversely with all outcomes assessed and was significantly associated with current smoking (P=0.04) and lower HPV titer (P=0.03).

HPV titer had a significant association with p16 expression (P<0.0001), which in turn had a positive association with all of the response and survival outcomes.

The combination of low HPV titer and increased expression of EGFR predicted lower survival, and low expression of p53 combined with increased expression of BCLXL was associated with poor survival.

"The combination of markers was an important indicator," said Bavna Kumar, one of the authors of the study. "This is a step in the direction of affecting future treatment."

David M. Kurnit, M.D., Ph.D., a co-author of both articles, disclosed a financial interest in SensiGen, a company that is developing HPV detection method used in the study. None of the other co-authors reported disclosures.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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